EP3484864A1 - Dérivés de pyrimidinone et leurs utilisations pour neutraliser l'activité biologique des chimiokines - Google Patents

Dérivés de pyrimidinone et leurs utilisations pour neutraliser l'activité biologique des chimiokines

Info

Publication number
EP3484864A1
EP3484864A1 EP17743287.9A EP17743287A EP3484864A1 EP 3484864 A1 EP3484864 A1 EP 3484864A1 EP 17743287 A EP17743287 A EP 17743287A EP 3484864 A1 EP3484864 A1 EP 3484864A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
chosen
piperazinyl
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP17743287.9A
Other languages
German (de)
English (en)
Inventor
Dominique Bonnet
Nelly FROSSARD
Jean-Luc Galzi
Christophe GUIGNABERT
Marcel Hibert
Frédéric SIMONIN
Sylviane Muller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre International De Recherche Aux Frontieres de la Chimie
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Strasbourg
Universite Paris Saclay
Original Assignee
Centre International De Rech Aux Frontieres de la Chimie
Centre International De Recherche Aux Frontieres de la Chimie
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Sud Paris 11
Universite de Strasbourg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre International De Rech Aux Frontieres de la Chimie, Centre International De Recherche Aux Frontieres de la Chimie, Centre National de la Recherche Scientifique CNRS, Institut National de la Sante et de la Recherche Medicale INSERM, Universite Paris Sud Paris 11, Universite de Strasbourg filed Critical Centre International De Rech Aux Frontieres de la Chimie
Publication of EP3484864A1 publication Critical patent/EP3484864A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to new pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines, in particular chemokine CXCL12.
  • the invention relates to the use of said compounds as a pharmacological tool or as a medicament, in particular for preventing and/or treating inflammation and inflammatory diseases, immune and auto-immune diseases, pain-related diseases, genetic diseases and/or cancer.
  • a pharmacological tool or as a medicament in particular for preventing and/or treating inflammation and inflammatory diseases, immune and auto-immune diseases, pain-related diseases, genetic diseases and/or cancer.
  • Chemokines are small proteins that play critical roles in the development and function of various tissues in vertebrates. As a rather general rule, chemokines and their G protein-coupled receptors display redundancy and binding promiscuity, i.e. several chemokines may bind to the same receptor, whereas a few chemokines play a pivotal and non-redundant homeostatic role. In the adult, they regulate the directional migration of leukocytes under normal and pathological conditions. They are associated with an extraordinary high number of diseases, including chronic inflammatory diseases, autoimmune diseases (lupus erythematosus), cancer, atherosclerosis and AIDS, and their receptors represent druggable targets. Indeed, classical drug design strategies aim at discovering chemokine receptor ligands, mainly antagonists, in order to regulate the associated functions. However, many antagonists have disappointingly failed clinical trials due to chemokine receptors redundancy.
  • the chemokine CXCL12 plays a pivotal role in normal and pathological situations, including brain development, hematopoiesis, and chronic inflammation1.
  • a group of innovative compounds belonging to the chalcone family that prevent CXCL12 from binding to its CXCR4 or CXCR7 receptors2-5, have been created with original mechanisms of action: they bind to the chemokine rather than to the receptor, and neutralize its biological activity.
  • Such molecules were termed“neutraligands” by analogy with neutralizing antibodies, and proved to have therapeutic potential. Indeed a small molecule,“chalcone-4”5 inhibits binding of CXCL12 to CXCR4 and CXCR7, inhibits intracellular calcium responses, blocks chemotaxis of human peripheral blood CD4+ lymphocytes and prevents CXCR4 internalization in response to CXCL12.
  • This chemical compound is also active in vivo in a mouse model of airway allergic eosinophilic inflammation in which it inhibits inflammatory infiltration in particular of eosinophils. Its activity in other pathologies involving the CXCL12/CXCR4 axis such as the WHIM syndrom or carcinogenesis has also been recently demonstrated6,7.
  • One of the objectives of the invention is to find novel compounds able to bind CXCL12 and to neutralize its activity in vivo.
  • the invention relates to a new class of pyrimidinone derivatives, and uses thereof for inhibiting the biological activity of chemokine CXCL12.
  • the invention also relates to pharmacological tools or pharmaceutical compositions comprising said new pyrimidinone derivatives for neutralizing CXCL12.
  • Another aspect of the invention relates to a method of treating a disease or a condition that involves CXCL12, comprising administration to a patient, in need of said treatment, of a compound according to formula (I) or a pharmaceutical composition comprising a compound according to formula (I).
  • the disease or condition that can be treated by the compounds of formula (I) as well as the pharmaceutical compositions thereof includes inflammation and inflammatory diseases, immune and auto-immune diseases, pain-related diseases, genetic diseases and/or cancer.
  • Non-limiting examples of the diseases that can be treated with the compounds or the compositions of the invention include atopic dermatitis, asthma, atopic rhinitis, atopic conjunctivitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), obliterative bronchiolitis and chronic lung allograft dysfunction (CLAD), hyperalgesia/pain, lupus, Sjögren disease, chronic inflammatory diseases such as rhumatoid arthritis, inflammatory bowel disease, WHIM syndrome, rare diseases associated with hypereosinophilia (such as hypereosinophilic syndromes, eosinophilic bronchiolitis, Churg-Strauss syndrome or eosinophilic granulomatosis with polyangeiitis).
  • a subject of the invention is a com ound havin the eneral formula (I):
  • A represents a cyclic or heterocyclic radical chosen from ;
  • said cyclic or heterocyclic radical may be substituted with substituents chosen from halogen such as F, I, Cl or Br ; (C 1 -C 10 ) alkyl ; OR with R representing H, (C 1 -C 10 ) alkyl, CF 3 ; CONHR’ with R’ representing H, (C 1 -C 6 )alkyl-NH 2 , a divalent hydrocarbon radical (-CH 2 -) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 -), cyclobutyl (C 4 H 7 -), cyclopentyl (C 5 H 9 -), cyclohexyl (C 6 H 11 -), morpholinyl
  • piperazinyl salt ( - ), phenyl (C 6 H 5 -), benzyl (C 6 H 5 CH 2 -), phenetyl (C 6 H 5 CH 2 CH 2 -), tolyl (C 6 H 4 CH 3 -), xylyl (C 6 H 3 (CH 3 ) 2 -), benzylidene (C 6 H 5 CH CH-), benzoyl (C 6 H 5 CO), biphenyl (or diphenyl) (C 12 H 9 -), naphtyl (C 10 H 7 -) or tetrazolyl ( ), and n being an integer from 0 to 5;
  • Y represents H ; (C 1 -C 10 )alkyl ; (CO)(C 1 -C 10 )alkyl ; aryl chosen from phenyl, benzyl, phenetyl, tolyl, xylyl, benzylidene or benzoyl;
  • X represents O, NH or CO
  • B1 and B2 are each independently H ; (C1-C10)alkyl ; CO(C1-C10)alkyl ; CF3 ; (CH 2 ) m NR a R b ; P(O)(OH) 2 ; (CH 2 ) p OCO(C 1 -C 10 )alkyl ; CO(CH 2 ) p NR a R b ; COCH[(CH 2 ) n OH][NR a R b ]; COCH[(CH 2 ) n NR a R b ][NR a R b ] ; COCH[(CH 2 ) n NR a R b ][NHCOR a ] ; COCH[(C 1 -C 10 )alkyl][NR a R b ] ; COCH(R d )NH(R e ) ; a divalent hydrocarbon radical (-CH 2 -) n linked covalently to a
  • R a and R b being each independently H, (C 1 -C 10 )alkyl and R d and R e being each independently H, (C 1 -C 10 )alkyl, (CH 2 ) n NR a R b , COCH 3 ,
  • B 1 and/or B 2 which is linked to said CO represents, independently, (C 1 -C 10 ) alkyl ; OR c ; C6H5 ; (PO)(OH)2 ; a (CH2)n group linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, morpholinyl salt, piperazinyl, piperazinyl salt, phenyl, benzyl, phenetyl, tolyl, xylyl, benzylidene, benzoyl, biphenyl, naphtyl, tetrazolyl, thiophen, pyrrol, pyrazol, oxazol, thiazol, oxadiazol, thiadiazol, pyrimidine, pyrazine, pyridazine ;
  • R c being H, (C 1 -C 10 ) alkyl, aryl chosen from phenyl, benzyl, phenetyl, tolyl, xylyl, benzylidene or benzoyl, and n being as defined previously,
  • B3, B4, B5 are each independently H ; halogen chosen from F, I, Cl or Br ; (C1-C10) alkyl ; OR; CONHR’ ; COOR a ; CN ; a divalent hydrocarbon radical (-CH 2 -) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 -), cyclobutyl (C 4 H 7 -), cyclopentyl (C 5 H 9 -), cyclohexyl (C 6 H 11 -), morpholinyl ), piperazinyl, piperazinyl salt ( ), phenyl (C 6 H 5 -), benzyl (C 6 H 5 CH 2 -), phenetyl (C6H5CH2CH2-), tolyl (C6H4CH3-), xylyl (C6H3(CH3)2-), benzylidene (C6H5CH
  • R representing H, (C 1 -C 10 ) alkyl, CF 3 ;
  • compound (I) is not the 4-(1,2-dihydro-6-(4-hydroxy-3- methoxyphenyl)-2-oxopyrimidin-4-yl)-2-methylbenzoic acid.
  • alkyl means any monovalent radical of a linear or branched hydrocarbon chain.
  • a (C1-C10) alkyl represents an alkyl having from 1 to 10 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, 2-ethylhexyl, n-nonyl, 3,5,5-trimethylhexyl, n-decyl, n-undecyl, n-dodecyl or n- octadecyl.
  • Preferred alkyls are methyl, ethyl, isopropyl and t-butyl.
  • compositions comprise, for example, tosylate, mesylate, hydrochloride, hydrobromide, tartrate, hydroiodide, fumarate, oxalate, sulfate, ethanesulfonate, citrate, trifluoroacetate, ascorbate, triflate, formate, acetate, maleate, propionate, furoate.
  • Tautomeric forms of compound (I) comprise the following compounds: .
  • A in formula (I) above, it is also possible for A to represent a cyclic or heterocyclic radical having 3 to 10 atoms, which may be saturated or not, which ma be substituted or not and which are for exam les the followin :
  • Said cycles may be substituted.
  • the substitution may substitute an H of a carbon atom or may substitute the H in NH groups.
  • substituents are halogen chosen from F, I, Cl or Br ; (C 1 -C 10 ) alkyl ; OR with R as defined previously ; CONHR’ with R’ as defined previously ; COOR a with R a as defined previously ; NR a R’ a with R a and R’ a as defined previously ; CN ; a divalent hydrocarbon radical (-CH 2 -) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 -), cyclobutyl (C 4 H 7 -), cyclopentyl (C 5 H 9 -), cyclohexyl (C 6 H 11 -), morpholinyl ), piperazinyl, piperazinyl salt ( ), phenyl (C 6 H 5 -
  • A is selected from phenyl, furanyl, pyridinyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may be substituted.
  • A is not pyrrolyl, pyridinyl, dihydropyrodinyl and indolyl.
  • X represents O or NH in the above mentioned compound (I)
  • B1 and B2 are each independently (CH2)mNRaRb ; CO(CH 2 ) p NR a R b ; COCH[(CH 2 ) n OH][NR a R b ]; COCH[(CH 2 ) n NR a R b ][NR a R b ] ; COCH[(CH 2 ) n NR a R b ][NHCOR a ] ; COCH[(C 1 -C 10 )alkyl][NR a R b ], then the NR a R b group represents NH 2 or NH +
  • A is a substituted phenyl group having the following formula:
  • a 1 , A 2 , A 3 , A 4 , A 5 are each independently H ; halogen chosen from F, I, Cl or Br ;
  • a 1 , A 2 , A 4 , B 4 , B 5 and Y represent H, and A 3 , A 5 , B 3 , X, B 1 and B 2 are as defined above.
  • A represents:
  • a 1 , A 2 , A 4 represent H
  • B 4 , B 5 and Y represent H, and,
  • a 3 , A 5 and B 3 are each independently H ; a halogen chosen from F, I or Cl ; an alkyl radical chosen from methyl, ethyl or isopropyl ; an OR group chosen from OH, OCH3, OC2H5 or OCF3 ; COOH ; CN ; a cyclic or heterocyclic compound chosen from cyclohexyl, morpholinyl, piperazinyl, piperazinyl salt or tetrazolyl ;
  • B 1 and B 2 are each independently H ; methyl, ethyl ; COCH 3 ; COCH(CH 3 ) 2 ; CF 3 ; CH 2 -CH 2 -NH 2 , CH 2 -CH 2 -NH +
  • n being as defined previously
  • B1 and/or B2 which is linked to said CO represents, independently, methyl, ethyl; OH, OCH 3 , OC 6 H 5 ; C 6 H 5 ; (PO)(OH) 2 ; a hydrocarbon radical (-CH 2 -) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from or , n being as defined previously.
  • the X linked to the B 2 group represents O and B 2 represents H.
  • X represents O
  • B 1 represents a (C 1 -C 10 ) alkyl
  • B 2 represents H. Examples of such compounds are those selected from the group wherein:
  • • A represents (38) • A represents 9) • A represents 0), • A represents 41), • A represents 2), • A represents 3), • A represents 4), • A represents (45), • A represents (46), • A represents (47), • A represents (48), • A represents ), • A represents (50), • A represents ,
  • compounds of general formula (I) are those selected from the group wherein:
  • compounds of formula (I) are selected in the group consisting of compounds (1), (2), (3), (5), (7), (8), (9) and their mixtures.
  • compounds of formula (I) are selected in the group consisting of compounds (1), (2) and (7).
  • Compound (1) is particularly preferred since it presents improved physicochemical properties, in particular in view of“chalcone-4” described in the state of the art5,6,7,8,9. In particular, its solubility is better than the solubility of“chalcone-4”.
  • a subject of the invention is also a compound of general formula (I) as defined above, a pharmaceutically acceptable salt thereof or a tautomeric form thereof, for use as a medicament.
  • the invention relates to compound of general formula (I) as defined above, a pharmaceutically acceptable salt thereof or a tautomeric form thereof, for use for inhibiting the biological activity of chemokine CXCL12.
  • the invention relates to compound of general formula (I) as defined above, a pharmaceutically acceptable salt thereof or a tautomeric form thereof, for the prevention and/or treatment of inflammation and inflammatory diseases, immune and auto-immune diseases, pain-related diseases, genetic diseases and/or cancer.
  • compositions comprising at least a compound of formula (I), a pharmaceutically acceptable salt thereof or a tautomeric form thereof, as defined above and optionally a pharmaceutically acceptable excipient or carrier.
  • the compound of formula (I), a pharmaceutically acceptable salt thereof or a tautomeric form thereof is a neutralizing agent of CXCL12, and acts as an active agent in the pharmaceutical composition of the invention.
  • the compounds or the compositions of the invention can also be used as a pharmacological tool.
  • pharmacological tool refers to a compound which functional properties allow to study how drugs interact with living organisms to produce a change in functions of interest, thereby allowing to study new drug composition and properties, interactions, toxicology, therapy, medical applications and antipathogenic capabilities.
  • the term refers to a compound which may be used to characterize potential targets for the development of novel medicines, e.g. characterize their native composition, activation mechanisms, physiological functions, and roles in patho-physiology and disease.
  • the present invention also relates to a composition as defined above, for use as a medicament.
  • the pharmaceutical composition further comprises one or more biologically active agents.
  • suitable biologically active agents include, but are not limited to, therapeutic agents such as anti-viral agents, anti-inflammatory agents, immunomodulatory agents, analgesics, antimicrobial agents, kinase inhibitors, signalling inhibitors, antibacterial agents, antibiotics, antioxidants, antiseptic agents, and combinations thereof.
  • the compound of formula (I) may be combined in one or more preparations for simultaneous, separate or sequential administration of the compound of formula (I) and the other active agent(s).
  • an inventive composition may be formulated in such a way that the compound of formula (I) and the other active agent(s) can be administered together or independently from each other.
  • a compound of formula (I) and the other active agent can be formulated together in a single composition. Alternatively, they may be maintained (e.g., in different compositions and/or containers) and administered separately.
  • active agents which can be used in combination with compound (I) of the invention are:
  • beta 2 receptor agonists including non exclusively : SABA (short acting beta2 agonists) : albuterol, levalbuterol, salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, clinbuterol, fenoterol, metaproterenol, bitolterol mesylate, ritodrine, isoprenaline, LABA (long acting beta2 agonists), salmeterol, formoterol, indacaterol, bambuterol, olodaterol, vilanterol, arformoterol etc...,
  • SABA short acting beta2 agonists
  • albuterol albuterol
  • levalbuterol salbutamol
  • levosalbutamol terbutaline
  • pirbuterol procaterol
  • clinbuterol fenoterol
  • metaproterenol bitolterol mesylate
  • ritodrine
  • ⁇ muscarinic antagonists anticholinergics like ipratropium, diphenhydramine, aclidinium bromide, LAMA (long acting muscarinic antagonists) including non exclusively tiotropium bromide, aclidinium etc...,
  • Anti-inflammatory corticosteroids oral, inhaled, topical
  • cortisol including non exclusively beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, etc, or oral like cortisol, cortisone, prednisone, prednisolone, methylprednisolone, hydrocortisone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone, etc...,
  • Antihistamines oral or topical including non exclusively hydroxyzine, diphenhydramine, chlorpheniramine, ketotifen, olopatadine, cetirizine, levocetirizine, ebastine, azelastine, fexofenadine, loratadine, desloratadine, mizolastine, etc...,
  • - Immunomodulators including non exclusively tacrolimus, pimecrolimus, everolimus, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, leflunomide, cyclophosphamide etc...,
  • Bio-actives including non exclusively omalizumab and anti-IgE antibodies, mepolizumab and anti-IL-5 antibodies, dupilumab and anti-IL-4 and anti-IL-13 treatments, belimumab and anti-BLyS agents, etc....,
  • Nonsteroidal anti-inflammatory drugs including non exclusively ibuprofen, naproxen, aspirine, acetaminophen, indomethacin, nabumetone, celecoxib, etc...,
  • Phosphodiesterase inhibitors including non exclusively roflumilast, theophylline and derivatives (aminophylline%), etc...,
  • Actives for pulmonary hypertension including non exclusively epoprostenol, bosentan, macitentan, iloprost, sildenafil, treprostinil, etc...,
  • the compounds, compositions and methods of the present invention can be used to treat inflammatory diseases or conditions or inflammations associated with:
  • an allergic disease including hives, urticaria, pollen allergy, dust mite allergy, venom allergy, cosmetics allergy, latex allergy, chemical allergy, drug allergy, insect bite allergy, animal dander allergy, stinging plant allergy, poison ivy allergy, allergic rhinitis, food allergy, etc;
  • a respiratory system disease including chronic lung disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis rhinitis, pulmonary arterial hypertension (PAH), rare diseases associated with hypereosinophilia (such as hypereosinophilic syndromes, eosinophilic bronchiolitis, Churg-Strauss syndrome or eosinophilic granulomatosis with polyangeiitis), obliterative bronchiolitis and chronic lung allograft dysfunction, etc;
  • PAH pulmonary arterial hypertension
  • a pain-related disorder including neuropathic or neurological pain, chronic pain, acute pain, migraine, headache inflammatory pain, post-operative pain, pain due to multiple sclerosis, Parkinson's disease or other neurological or autoimmune disorder, hyperalgesia induced by stress or by opioids or other;
  • an auto-immune disease including eosinophilic granulomatosis with polyangiitis or polyarteritis nodosa asthma, hypersensitivity pneumonitis, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, lupus, Sjögren disease, non-limiting examples of auto-immune renal diseases including antibody mediated glomerulopathy as acute glomerulonephritis, nephritis associated with systemic lupus erythematosus, nephritis associated with other systemic diseases, non-limiting examples of auto-immune gastrointestinal diseases including Crohn's Disease, ulcerative colitis, coeliac disease, Whipple's disease, non-limiting examples of auto- immune hepatobiliary diseases including auto-immune hepatitis, alcohol-induced hepatitis, non- limiting examples of auto-immune skin diseases including psoriasis, atopic dermatitis
  • the compound of formula (I) and the composition of the invention can be used for prevention and/or treatment of a disease chosen in the group comprising asthma, atopic dermatitis, allergic rhinitis, atopic conjunctivitis, rhinoconjunctivitis, chronic obstructive pulmonary disease (COPD), lupus, Sjögren syndrome, hyperalgesia/pain, pulmonary hypertension (PH), obliterative bronchiolitis and chronic lung allograft dysfunction, chronic inflammatory diseases (such as rhumatoid arthritis), inflammatory bowel disease, WHIM syndrome (Warts, Hypogammaglobulinemia, Immunodeficiency and Myelokathexis syndrome) and rare diseases associated with hypereosinophilia (such as hypereosinophilic syndromes, eosinophilic bronchiolitis, Churg-Strauss syndrome or eosinophilic granulomatosis with polyangeiitis).
  • the present invention also relates to a method of treating a disease or a condition that involves CXCL12, comprising administering to a patient, in need of said treatment, a compound according to formula (I), a pharmaceutically acceptable salt thereof or a tautomeric form thereof, or a pharmaceutical composition comprising a compound of formula (I), a salt thereof or a tautomeric form thereof, in a therapeutically effective amount.
  • the term“treatment” and the related terms“treat” and“treating” are used herein to characterize a method or process that is aimed at (1) delaying or preventing the onset of a disease, disorder or condition; (2) slowing down or stopping the progression, aggravator deterioration of the disease, disorder or condition; (3) bringing about amelioration of the symptoms of the disease, disorder or condition; or (4) curing the disease, disorder or condition.
  • the term refers to both prophylactic or preventive treatment as well as curative or palliative treatment.
  • the term encompasses situations where disease, disorder or condition is already being experienced by a subject or patient, as well as situations where disease, disorder or condition is not currently being experienced but is expected to arise.
  • patient refers to a warm-blood animal, preferably a human being, i.e. a subject of any gender and at any stage development (i.e. neonate, infant, juvenile, adolescent, adult).
  • Administration of the compounds of formula (I) of the invention, pharmaceutically acceptable salts thereof or tautomeric forms thereof, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, by the oral, sublingual, nasal, parenteral (intravenous, intramuscular, or subcutaneous), topical, transdermal, intravaginal, intravesical, or rectal routes, in the form of solid, semi-solid, lyophilized powder or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, sirup, nebulizations, aerosols or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • a compound of the invention which constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.
  • the therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge.
  • Compounds of formula (I) can be prepared using art recognized methods.
  • Figure 2 Atopic dermatitis
  • FIG. 2A In vivo effect of a topical treatment with chalcone 4 and compound (1).
  • Mouse ears were treated with MC903 (calcipotriol, 2nmol/ear or 4 nmol/ear) or its solvent (ethanol EtOH) together with 350 ⁇ mol/kg chalcone 4 (upper row of images) or compound (1) (lower row of images) or solvent (acetone/olive oil 50/50, AOO).
  • Chalcone 4 and compound (1) were dissolved in AOO and administered topically 2h before each MC903 application.
  • MC903 was dissolved in EtOH and topically applied.
  • Figure 3 COPD
  • MRL/lpr mice 11-13 week-old received intravenously a single administration of either compound (1) or chalcone 4-Phosphate or indicated molecules in saline (100 ⁇ g/mouse of each).
  • the control group received saline only.
  • Figure 5 Hyperalgesia
  • Figure 6 Pulmonary hypertension (PH)
  • FIG. 6A In vivo effect of chalcone-4 and compound (1) in the SU-5416 (20 mg/kg)/Hypoxia (SuHx) rat model of PH on total pulmonary vascular resistance, cardiac output and right ventricular hypertrophy.
  • Male Wistar rats (100g upon arrival in the laboratory; Janvier Labs, France) served as experimental subjects.
  • SU-5416 (20 mg/kg) was injected subcutaneously and the rats were placed in normobaric hypoxia (10% FiO 2 ) for 3 weeks for PH to develop, and were then left for 2 weeks in normoxia. Rats were treated either with chalcone-4 or compound (1) at a dose of 100 mg/kg i.p. as compared with vehicle-treated SuHx rats.
  • CTR pulmonary vascular resistance
  • CO cardiac output
  • RVH right ventricular hypertrophy
  • the bar graph represents means ⁇ SEM.
  • Figure 6B Representative photographs of hematoxylin-eosin (H&E) staining of lung paraffin-sections of SuHx rats treated with chalcone-4 and compound (1) when compared with the SuHx rats treated with vehicle.
  • CTR control rats with no PH.
  • Scale Bar 50 ⁇ m.
  • Figure 6C Representative photographs of alpha smooth muscle-actin ( ⁇ SMA) staining of lung paraffin-sections of SuHx rats treated with chalcone-4 and compound (1) when compared with the SuHx rats treated with vehicle.
  • CTR control rats with no PH.
  • Scale Bar 50 ⁇ m.
  • Reagents were obtained from commercial sources and used without any further purification. Thin-layer chromatography was performed on silica gel 60F 254 plates. Flash chromatography was performed on silica gel cartridges (SiliaSepTM Flash cartridges silica, 40-63 ⁇ m) or RP18 prepacked columns (PuriFlash® 30 ⁇ m, Interchim) prepacked columns using a Spot II Ultimate apparatus from Armen Instrument.
  • Reagents and conditions (i) urea, HCl, dioxane/EtOH, 100 °C, 2 h, 43%.
  • the product was purified on silica gel (30% EtOAc in n-heptane), followed by recrystallization from EtOAc and heptane to afford the desired product (536 mg, 1.26 mmol, 36%) as a yellow solid.
  • Compound 22c is obtained from compound 22b according to general procedure B.
  • the reaction mixture was poured in a mixture of ice and water and extracted four times with EtOAc. The collected organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography on a 25 g silica gel column (hexanes/EtOAc 10:0 to 10:10 (v/v) in 30 min) to afford a colorless oil (270 mg, 1.3 mmol, 12 %).
  • the crude product was purified by flash chromatography on a 80 g silica gel column (CH 2 Cl 2 /MeOH 1:0 to 9:1 (v/v) in 60 min) to afford a pale yellow solid (6.72 g, 30.8 mmol, 68 %).
  • the combined organic layers were extracted with 10% aq. NaOH.
  • the combined aqueous layers were acidified with 2N aq. HCl to pH 9.
  • the product was extracted three times with EtOAc.
  • the combined organic layers were washed with a saturated aq. Na 2 CO 3 solution, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford a brown oil (0.928 g, 5.09 mmol, 33 %).
  • Compound 25c is obtained from compound 25b according to general procedure C.
  • the crude product was purified by flash chromatography on silica gel column (hexanes/EtOAc 10:0 to 10:10 (v/v) in 30 min) to afford a colorless liquid (0.70 g, 3.61 mmol, 32%).
  • Vanillin 131 mg, 0.862 mmol, 1.02 equiv was added to DIMCARB (2.16 mL, 16.9 mmol, 20 equiv) in DCE (0.7 mL) at ambient temperature with stirring.2-Chloro-5-acetylpyridine (131 mg, 0.845 mmol, 1 equiv) was added in a single portion to the reaction mixture. The reaction was stirred overnight at 50 °C. The solvent was evaporated, and the crude solid was treated with 2N H 2 SO 4 (neutralization of the remaining amine).
  • the crude product was purified by flash chromatography on a 12 g silica gel column (hexanes/EtOAc 10:0 to 10:10 to 0:10 (v/v) in 30 min) to afford a yellow solid (190 mg, 0.637 mmol, 75 %).
  • Step 1 synthesis of (2E)-3-(4-hydroxy-3-methoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (“60a”)
  • Vanillin (1.02 eq., 711 mg, 0.671 mL, 4.67 mmol) was added to DIMCARB (15 eq., 9221 mg, 8.78 mL, 68.7 mmol) in DCE (3.63 mL) at ambient temperature with stirring. Gas was evolved. 2-acetyl pyrrole (1 eq., 500 mg, 4.58 mmol) was added in a single portion to the reaction mixture. The reaction was stirred overnight at 50 °C.
  • Step 2 synthesis of (2E)-3-(4-hydroxy-3-methoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (60)
  • Example 2 In vitro study of compounds (1) to (10), (28), (33) (59) and 60 of general formula (I) The inhibition of the CXCR4-CXCL12 binding was studied with compounds (1) to (10) of general formula (I) and with three other compounds, named (A) to (C), having a structure close to formula (I) but which do not belong to formula (I).
  • Said three compounds (A) to (C) are respectively the following:
  • - A is a phenyl group having the followin formula:
  • a 1 , A 2 , A 4 , B 3 , B 4 , B 5 and Y represent H
  • a 3 , A 5 , B 1 and B 2 are defined in table 2 below.
  • FRET fluorescence resonance energy transfer
  • the compounds were tested at a concentration of 10 ⁇ K i (inhibition constant).
  • the CXCR4 antagonist, T134 (20 ⁇ M) was used as a control in both incubation protocols. Data obtained were consistent with a binding to the chemokine and not to its receptor. Consequently, all selected compounds are indeed CXCL12 chemokine neutraligands and behave as chalcone-4. The neutralizing properties of the compounds are thus confirmed.
  • compound (1) was selected for in vivo studies.
  • Example 4 In vivo biological evaluation of compound (1) in a mouse model of airway allergic eosinophilic inflammation
  • Asthma is one of the most common chronic inflammatory diseases, and a major health problem with 300 million cases worldwide, imposing a considerable burden on society in morbidity, quality of life, and healthcare costs.
  • great advances have been made in the understanding of the mechanisms of chronic inflammation in asthma, there has been little progress in developing new medications, and the association between inhaled glucocorticoids and the bronchorelaxant ß2- agonists form the gold standard, first-line therapy of persistent asthma to alleviate bronchial inflammation together with bronchoconstriction.
  • glucocorticoid therapy has potential to cause systemic side effects including dysphonia, topical candidiasis, lung infection, intraocular pressure and cataracts, and skeletal effects with osteoporosis in elderly and growth deceleration in children.
  • systemic side effects including dysphonia, topical candidiasis, lung infection, intraocular pressure and cataracts, and skeletal effects with osteoporosis in elderly and growth deceleration in children.
  • chemokine and their receptors may be targeted in asthma and atopic diseases.
  • mice were sensitized to ovalbumin (OVA) and challenged 3 times with OVA or saline at 24 h interval.
  • OVA ovalbumin
  • Treatments with each compound 300 nmol/kg in 10% PBS/Cdx were administered by the intranasal route 2 h before each challenge.
  • Bronchoalveolar lavage was performed 24 h after the last challenge, and eosinophil, macrophage, neutrophil and lymphocyte numbers quantified.
  • the reference chalcone 4 had an IC50 higher than 500 nmol/kg, but the actual value could not be determined precisely because the solubility threshold was reached at this concentration in PBS/Cdx.
  • the novel pyrimidinone (1) proved to be more soluble, and its calculated IC 50 was 300 nmol/kg.
  • the selectivity of (1) was also evaluated towards two other chemokines, namely CCL17 and CCL22, with no activity at 5 ⁇ M (data not shown).
  • pyrimidinone (1) is a novel CXCL12 neutraligand, one of the most potent and soluble in our in vitro SAR (structure-activity relationship) studies and the most active to date in the in vivo inhibition of allergic eosinophilic airway inflammation in mice.
  • mice were administered intranasally with LPS (lipopolysaccharide from E. coli, O55B5, 1 ⁇ g, Sigma Aldrich) or saline.
  • LPS lipopolysaccharide from E. coli, O55B5, 1 ⁇ g, Sigma Aldrich
  • saline aline
  • Treatments with (1) or Chalcone-4 (350 ⁇ mol/kg) in 1% CMC (carboxymethylcellulose) were administered by the intraperitoneal route 2 h before LPS instillation.
  • Bronchoalveolar lavage was performed 24 h after LPS, and neutrophil, lymphocyte, eosinophil and macrophage numbers quantified.
  • the reference chalcone-4 showed 30% inhibition of neutrophil recruitment at 350 ⁇ mol/kg.
  • the novel pyrimidinone (1) reduced neutrophil recruitment by 43% (Figure 3).
  • compound (1) is a novel CXCL12 neutraligand, one of the most potent and soluble in our in vitro SAR studies and the most active to date in the in vivo inhibition of airway neutrophilic inflammation in mice.
  • MRL/lpr lupus prone mice which is the most commonly studied mouse model of the disease, bears an autosomic recessive mutation in the gene encoding Fas15.
  • the MRL+/+ background is responsible for the development of autoimmune kidney disease, and the lymphoproliferation (lpr)/Fas mutation converts a mild nephritis into a much severe disease, with a 50% mortality rate at 24 weeks of age13.
  • MRL/lpr mice Based on the fact that compared to normal mice (e.g. CBA/J mice), MRL/lpr mice show an elevated number of leukocytes in their blood, which is easy to measure, we have established a rapid, robust and reliable routine assay allowing to evaluate in vivo properties of compounds by measuring the decrease of this abnormal peripheral hypercellularity a few days after administration14.
  • mice The test was as described previously (Schall et al., 2012; Briand et al., 2014). All experimental protocols were carried out with the approval of the French Institutional Animal Care and Use Committee. Briefly, groups of 11-13 week-old MRL/lpr mice (same age and sex, male or female) were injected intravenously (retro-orbital route) with 100 ⁇ g of each molecule per 100 ⁇ L of 9 ⁇ NaCl: chalcone 4-phosphate or compound (1) (in PBS/Cdx 10%), or cyclophosphamide, hydroxychloroquine, amethopterin, azathioprine, or mycophenolate mofetil (8-10 mice/condition).
  • mice received 100 ⁇ L of 9 ⁇ NaCl only. After 5 days, mice were bled individually. Red blood cells were lysed using EasyLyse reagent (DAKO, ref. S2364) according to the manufacturer’s protocol. After centrifugation, white blood cells (WBCs) resuspended in phosphate buffer saline containing fetal calf serum were stained with acridine orange / propidium iodide and counted using a LUNA FL apparatus (logos Biosystems, Annandale, USA). The number of living WBCs in each group was compared to the one counted in the control group and the decrease of peripheral cell number was calculated.
  • DAKO EasyLyse reagent
  • mice To avoid any bias due to groups of mice, the results mixed from several independent experiments are presented. The results are expressed as the mean decreased of peripheral WBCs percentage ⁇ SEM. Statistical differences were determined using the unpaired t test. Statistical results were calculated using the graphPad Prism software.
  • Example 8 In vivo evaluation of compound (1) in the model of fentanyl-induced hyperalgesia
  • great advances have been made in the understanding of mechanisms that underlie pain, there has been little progress in developing new analgesics, and systemic administration of opiate analgesics such as morphine still remains the most effective means of alleviating severe pain across a wide range of conditions.
  • opiate treatments are associated with several side effects including the development of pain hypersensitivity (hyperalgesia), which have been proposed to be responsible for the decrease in the efficacy of treatment over time (tolerance).
  • hypersensitivity hypersensitivity
  • chemokine and their receptors are involved in these phenomena20.
  • mice housed in groups of five per cage under a 12h / 12h light / dark cycle at a constant temperature (21 ⁇ 1°C) with free access to food and water. They were habituated to the experimental room and handled for one week before starting experiments. Every mouse was used only once.
  • Analgesia and hyperalgesia induced by fentanyl were evaluated as previously described16.
  • a dose of fentanyl was injected four times (4x60 ⁇ g.kg-1 , s.c.) at 15 min intervals, which mimics its use in human surgery.
  • the nociceptive threshold of naive and treated mice was assessed in the tail immersion test17 by measuring the latency time to withdraw their tail from a thermostated (48 ⁇ 0.5°C) water bath.
  • an analgesic effect increase of tail withdrawal latency
  • PVR pulmonary vascular resistance
  • PAP pulmonary arterial pressure
  • the activity of compound (1) vs chalcone-4 was evaluated in an animal model of pulmonary hypertension (PH) (by convention, animal models are still referred to as having PH rather than PAH): the SU-5416 (20 mg/Kg)/Hypoxia rat model.
  • Chalcone-4 and compound (1) 100 mg/kg/day were prepared in carboxymethylcellulose (CMC 1% in saline) and administered I.P. Rats were treated for 3 weeks in a curative protocol, and were then left for 2 weeks in normoxia. An additional group of healthy rats with no PH was used as the control group (CTR).
  • CTR control group
  • PH was induced by a single subcutaneous injection of SU5416 (20mg/kg) in Wistar rats, followed by a 3-week exposure to chronic hypoxia (10% FiO 2 ).
  • Right ventricular structure and function was assessed by echocardiography using the GE Vivid 9 ultrasound.
  • echocardiography measurements of each rat have been performed to validate the presence of PH in animals (acceleration time/ejection time). Then, the rats were randomized by numbering the animals from 1 to 4 in each cage at the beginning of the study, and then looking at a random number table. Each rat has been treated by intraperitoneal administration. At the end of the treatment period, a right heart catheterization (RHC) was performed to determine the PH severity and the cardiac function.
  • RHC right heart catheterization
  • RHC Right heart catheterization
  • RVH right ventricular hypertrophy
  • the thorax was opened and the left lung immediately removed and frozen.
  • the right lung was fixed in the distended state with formalin buffer.
  • the right ventricular hypertrophy assessed by the Fulton index [weight ratio of right ventricle (RV) and (left ventricle (LV) + septum)] and the percentage of wall thickness [(2 ⁇ medial wall thickness/ external diameter) ⁇ 100] and of muscularized vessels were determined as previously described21.
  • the data are expressed as means ⁇ SEM. Statistical significance was tested using the nonparametric Mann-Whitney test or two-way ANOVA with Bonferroni post hoc tests. Significant difference was assumed at a p value of less than 0.05.
  • TPVR total pulmonary vascular resistance
  • chalcone-4 and compound (1) substantially attenuated the pulmonary vascular remodeling in the SuHx rat model ( Figures 6B and 6C). Eight weeks after the SU-5416 administration, in SuHX rats treated with vehicle, a pronounced pulmonary vascular remodeling was noted with occluded distal pulmonary arteries, that was attenuated in SuHx rats treated with chalcone-4 and compound (1).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'objet de la présente invention est un composé de la formule générale (I), son sel pharmaceutiquement accepté ou un tautomère de celui-ci, où A, B3, B4, B5, Y, X, B1 et B2 sont tels que définis dans les déclarations 1 à 10. Un autre objet de l'invention est le composé tel que défini ci-dessus pour une utilisation en tant que médicament, en particulier pour prévenir et/ou traiter une inflammation et des maladies inflammatoires, de maladies immunitaires et auto-immunes, de maladies liées à la douleur, de maladies génétiques et/ou du cancer.
EP17743287.9A 2016-07-13 2017-07-13 Dérivés de pyrimidinone et leurs utilisations pour neutraliser l'activité biologique des chimiokines Pending EP3484864A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16305908 2016-07-13
PCT/EP2017/067775 WO2018011376A1 (fr) 2016-07-13 2017-07-13 Dérivés de pyrimidinone et leurs utilisations pour neutraliser l'activité biologique des chimiokines

Publications (1)

Publication Number Publication Date
EP3484864A1 true EP3484864A1 (fr) 2019-05-22

Family

ID=56507548

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17743287.9A Pending EP3484864A1 (fr) 2016-07-13 2017-07-13 Dérivés de pyrimidinone et leurs utilisations pour neutraliser l'activité biologique des chimiokines

Country Status (6)

Country Link
US (1) US11046657B2 (fr)
EP (1) EP3484864A1 (fr)
JP (2) JP7092742B2 (fr)
CN (1) CN110049974A (fr)
CA (1) CA3030232A1 (fr)
WO (1) WO2018011376A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11046657B2 (en) * 2016-07-13 2021-06-29 Centre National De La Recherche Scientifique Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines
CN109824624A (zh) * 2019-03-26 2019-05-31 浙江大学 含吗啉环的查尔酮类化合物及其制备和应用
WO2020257261A1 (fr) 2019-06-17 2020-12-24 Northwestern University Hétérocycles substitués servant d'agents de ciblage de c-myc
CN111217862B (zh) * 2020-02-26 2023-01-31 陕西科技大学 一种4-芳基-6-二茂铁基-3,4-二氢嘧啶-2(1h)-酮的制备方法
CA3184767A1 (fr) 2020-06-26 2021-12-30 Raqualia Pharma Inc. Methode de selection d'un patient cancereux pour lequel une polytherapie d'un retinoide et d'un agent de traitement du cancer sera efficace, et medicament combine d'un retinoide et d'un agent de traitement du cancer

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007048064A2 (fr) 2005-10-21 2007-04-26 Exelixis, Inc. Aminopyrimidines en tant que modulateurs de caseine kinase ii (ck2)
JP2010525062A (ja) 2007-04-25 2010-07-22 エグゼリクシス， インコーポレイテッド Ｐｉｍモジュレーターとしてのピリミジノン類
AU2008253684B2 (en) 2007-04-25 2014-02-27 Exelixis, Inc. Pyrimidinones as Casein kinase II (CK2) modulators
GB0810228D0 (en) 2008-06-04 2008-07-09 Spear Therapeutics Ltd Novel compounds
WO2010151799A2 (fr) * 2009-06-26 2010-12-29 University Of Massachusetts Composés de modulation des protéines de liaison à l'arn et applications associées
EP2480086A4 (fr) * 2009-09-25 2013-03-20 N30 Pharmaceuticals Inc Nouveaux composés dihydropyrimidine-2(1h)-ones en tant qu'inhibiteurs de la s-nitrosoglutathion réductase
JP2012006869A (ja) * 2010-06-25 2012-01-12 Ono Pharmaceut Co Ltd ピリミジノン化合物およびその医薬用途
WO2012039718A1 (fr) * 2010-09-24 2012-03-29 N30 Pharmaceuticals, Llc Composés innovants de dihydropyrimidine-2(1h)-un en tant qu'antagonistes des récepteurs de neurokinine-3
US11046657B2 (en) * 2016-07-13 2021-06-29 Centre National De La Recherche Scientifique Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines

Also Published As

Publication number Publication date
CN110049974A (zh) 2019-07-23
US20200181093A1 (en) 2020-06-11
CA3030232A1 (fr) 2018-01-18
JP7092742B2 (ja) 2022-06-28
WO2018011376A1 (fr) 2018-01-18
US11046657B2 (en) 2021-06-29
JP2019524738A (ja) 2019-09-05
JP2022105013A (ja) 2022-07-12

Similar Documents

Publication Publication Date Title
US11046657B2 (en) Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines
US11026926B2 (en) Substituted bicyclic compounds as bromodomain inhibitors
CN107207474B (zh) 被取代的杂环作为溴结构域抑制剂
US9765039B2 (en) Biaryl derivatives as bromodomain inhibitors
CN107406438B (zh) 溴结构域的抑制剂
US9278940B2 (en) Cyclic amines as bromodomain inhibitors
JP5578083B2 (ja) ２ｈ−クロメン化合物及びその誘導体
EP3227280B1 (fr) Pyridines substituées comme inhibiteurs de bromodomaine
JP5038905B2 (ja) 医学的障害の治療用のｃｘｃｒ４拮抗薬
JP6903585B2 (ja) 補体関連疾患の治療のための組成物および治療方法
CA2966452A1 (fr) Composes bicycliques substitues utilises comme inhibiteurs de bromodomaine
CN111032658B (zh) 作为C5a抑制剂的5-5稠合环类
CN110997674A (zh) 作为C5a抑制剂的6-5稠合环类
JP6894902B2 (ja) Ｃｆｔｒ制御因子及びこの使用方法
US20230132808A1 (en) Wnt/cbp/catenin signaling pathway inhibitors and uses thereof
US20190231751A1 (en) Treatment of fibrotic disorders with jun n-terminal kinase inhibitors
TW202327622A (zh) 用於治療與呼吸道病毒感染相關的細胞介素釋放相關病症的ｉｒａｋ抑制劑

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20190211

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20210212

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: CENTRE INTERNATIONAL DE RECHERCHE AUX FRONTIERES DE LA CHIMIE

Owner name: UNIVERSITE PARIS-SACLAY

Owner name: UNIVERSITE DE STRASBOURG

Owner name: INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)

Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - CNRS